A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

中文翻译：

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PLCG2 保护性变体 p.P522R 调节轻度认知障碍患者的 tau 病理学和疾病进展。


在小胶质细胞中高度表达的磷脂酶-C-γ2 (PLCG2) 编码酶基因中发现了一种罕见的编码变体 (rs72824905, p.P522R)，可预防阿尔茨海默病 (AD)。为了探索这种变异的保护性质，我们采用潜在过程线性混合模型来检查 p.P522R 与 3595 名 MCI 患者和基于人群的研究中的 10,097 名个体的纵向认知能力下降之间的关系。此外，在 1261 名 MCI 患者中评估了 pTau181、总 tau 和 Aβ1-42 与 CSF 水平的关联。我们发现，与非携带者相比，携带 p.P522R 变体的 MCI 患者认知能力下降速度较慢，并且这种效应是由脑脊液中较低的 pTau181 水平介导的。 p.P522R 与认知能力下降和 pTau181 的关联效应大小与 APOE-ε4 相似，APOE-ε4 是 AD 最强的遗传风险因素。有趣的是，p.P522R 的保护作用在 Aβ1-42 水平较低的 MCI 患者中更为明显，表明 PLCG2 在淀粉样蛋白病理反应中发挥作用。与这一假设相符，我们在基于人群的研究中观察到 PLCG2 变体对认知能力下降没有保护作用，这可能是因为与 MCI 患者相比，这些样本中淀粉样蛋白阳性的患病率较低。关于潜在的生物学基础，我们使用无监督的共调控网络分析确定了一个将 PLCG2 连接到 APOE 和 TREM2 的共表达蛋白网络。该网络高度富集补体级联和疾病相关小胶质细胞中差异表达的基因。我们的数据显示，p。PLCG2 中的 P522R 通过在淀粉样蛋白病理存在的情况下减轻 tau 病理来减少 AD 疾病的进展，从而维持认知功能。靶向 PLCG2 酶可能为治疗 AD 提供新的治疗方法。